U.S. Pat. Nos. 4,024,175 and 4,087,544, which are herein incorporated by reference, disclose novel cyclic amino acids of Formula A 
wherein R1 is a hydrogen atom or a lower alkyl radical, and n is 4, 5, or 6 and the pharmacologically compatible salts thereof.
The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions, and thus are useful in treating geriatric patients. Particularly valuable is 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin).
Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson""s disease, Huntington""s Chorea, and dyskinesia (Saletu B., et al., International Journal of Clinical Pharmacology, Therapy and Toxicology, 1986;24:362-373). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man.
U.S. Pat. No. 5,084,479 discloses the use of gabapentin in neurodegenerative disorders. U.S. Pat. No. 5,025,035 discloses the use of gabapentin in depression. U.S. Pat. No. 5,510,381 discloses the use of gabapentin in mania and bipolar disorders.
The aforementioned compounds of Formula A including gabapentin have been prepared from a compound of formula 
wherein R2 is an alkyl radical containing up to eight carbon atoms, and n is as defined above by well-known standard reactions such as, for example, the Hofmann, Curtius, or Lossen rearrangements into the amino derivatives of Formula A. Although these reactions provide the target compounds, they require a large number of synthetic steps and in some cases involve potentially explosive intermediates.
U.S. Pat. No. 4,152,326 discloses cyclic sulphonyloxyimides of formula 
wherein R2 is a saturated, straight-chained, branched or cyclic lower aliphatic radical or an unsubstituted or substituted aryl radical, and n is 4, 5, or 6, which can be converted into a compound of Formula A. Again, similar to the previous processes, this process requires a large number of synthetic steps to obtain a compound of Formula A. Finally, all of the previous processes require as the penultimate step conversion of an intermediate salt of the target compound to an amino acid of Formula A.
U.S. Pat. Nos. 5,132,451, 5,319,135, 5,362,883, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, and 5,149,870 disclose additional processes and intermediates for preparing gabapentin. These processes require a number of steps and in some cases utilize large quantities of hazardous materials.
The object of the present invention is an improved process for preparing gabapentin employing a novel synthesis.
Further, we have unexpectedly found that gabapentin can be prepared from novel intermediates in fewer steps and higher yields than the previous methods. Moreover, the present method proceeds from inexpensive starting materials and is amenable to large-scale synthesis.
Accordingly, a first aspect of the present invention is an improved process for the preparation of the compound of Formula I 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula V 
xe2x80x83wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV 
xe2x80x83wherein R is as defined above;
Step (c) treating a compound of Formula IVa 
wherein R1a is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III 
xe2x80x83wherein R1a is as defined above;
Step (d) treating the compound of Formula IIIa 
xe2x80x83with an acid in a solvent to afford the compound of Formula II 
xe2x80x83or treating a compound of Formula IIIb 
xe2x80x83wherein R1b is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb 
xe2x80x83with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc 
xe2x80x83with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II;
Step (e) treating the compound of Formula IVa-1 
xe2x80x83with an acid in a solvent to afford the compound of Formula IVb or treating a compound of Formula IVa-2 
xe2x80x83wherein R1a-2 is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula IVb; and
Step (f) treating either the compound of Formula IVb or the compound of Formula IVc or the compound of Formula II with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula I.
A second aspect of the present invention is an improved process for the preparation of a compound of Formula IV 
wherein R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula V 
xe2x80x83wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV.
A third aspect of the present invention is an improved process for the preparation of a compound of Formula III 
wherein R1a is alkyl which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula V 
xe2x80x83wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV 
xe2x80x83wherein R is as defined above; and
Step (c) treating a compound of Formula IVa 
xe2x80x83wherein R1a is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III.
A fourth aspect of the present invention is an improved process for the preparation of the compound of Formula II 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula V 
xe2x80x83wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV 
xe2x80x83wherein R is as defined above;
Step (c) treating a compound of Formula IVa 
xe2x80x83wherein R1a is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III 
xe2x80x83wherein R1a is as defined above; and
Step (d) treating the compound of Formula IIIa 
xe2x80x83with an acid in a solvent to afford the compound of Formula II or treating a compound of Formula IIIb 
xe2x80x83wherein R1b is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb 
xe2x80x83with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc 
xe2x80x83with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II.
A fifth aspect of the present invention is an improved process for the preparation of the compound of Formula IVb 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula IVa 
xe2x80x83wherein X is halo or sulfonate and R1a is alkyl, in the presence of a solvent to afford a compound of Formula IVa 
xe2x80x83wherein R1a is as defined above; and
Step (c) treating a compound of Formula IVa with an acid or base in a solvent to afford the compound of Formula IVb
A sixth aspect of the present invention is an improved process for the preparation of the compound of Formula I 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula VIII 
xe2x80x83wherein X is halo or sulfonate and R2 is alkyl in the presence of a solvent to afford a compound of Formula IX 
xe2x80x83wherein R2 is alkyl;
Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X 
xe2x80x83wherein R2 is as defined above;
Step (d) treating a compound of Formula IX with an acid in the presence of a solvent to afford the compound of Formula IVb 
xe2x80x83or treating a compound of Formula X with an acid in the presence of a solvent to afford the compound of Formula II 
Step (e) treating either the compound of Formula IVb or Formula II with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula I
A seventh aspect of the present invention is an improved process for the preparation of a compound of Formula IX 
wherein R2 is alkyl which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula VIII 
xe2x80x83wherein X is halo or sulfonate and R2 is alkyl in the presence of a solvent to afford a compound of Formula IX.
An eighth aspect of the present invention is an improved process for the preparation of a compound of Formula X 
wherein R2 is alkyl which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula VIII 
xe2x80x83wherein X is halo or sulfonate and R2 is alkyl in the presence of a solvent to afford a compound of Formula IX 
xe2x80x83wherein R2 is alkyl; and
Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X.
A ninth aspect of the present invention is an improved process for the preparation of the compound of Formula II 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula VIII 
xe2x80x83wherein X is halo or sulfonate and R2 is alkyl in the presence of a solvent to afford a compound of Formula IX 
xe2x80x83wherein R2 is alkyl;
Step (c) treating a compound of Formula IX with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula X 
xe2x80x83wherein R2 is as defined above; and
Step (d) treating a compound of Formula X with an acid in the presence of a solvent to afford the compound of Formula II.
A tenth aspect of the present invention is an improved process for the preparation of the compound of Formula IVb 
which comprises:
Step (a) treating the compound of Formula VII 
xe2x80x83with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI 
Step (b) treating the compound of Formula VI with a compound of Formula VIII 
xe2x80x83wherein X is halo or sulfonate and R2 is alkyl in the presence of a solvent to afford a compound of Formula IX 
xe2x80x83wherein R2 is alkyl; and
Step (c) treating a compound of Formula IX with an acid in the presence of a solvent to afford the compound of Formula IVb
An eleventh aspect of the present invention is a novel compound of Formula IV 
wherein R1 is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl.
A twelfth aspect of the present invention is a novel compound of Formula IX 
wherein R2 is alkyl.
A thirteenth aspect of the present invention is a novel compound of Formula X 
wherein R2 is alkyl.
In this invention, the term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon group having from one to twelve carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, and the like.
xe2x80x9cAlkali metalxe2x80x9d is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
xe2x80x9cAlkaline-earth metalxe2x80x9d is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like.
xe2x80x9cHaloxe2x80x9d is halogen which is fluorine, chlorine, bromine, or iodine.
xe2x80x9cSulfonatexe2x80x9d is tosyl, mesyl, phenylsulfonate, chlorophenylsulfonate, bromophenylsulfonate, methoxyphenylsulfonate, and the like.
xe2x80x9cHigher order aminexe2x80x9d is methylamine, dimethylamine, methylethylamine, diethylamine, and the like.
xe2x80x9cAmine cationxe2x80x9d is 
wherein R, R1, R2, R3, are the same or different and each is hydrogen, alkyl of from 1 to 8 carbon atoms, phenyl, tolyl, and the like.
The compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of thee forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M., et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977;66:1-19).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethmolamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M., supra.).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acids for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
U.S. Pat. Nos. 4,894,476 and 4,960,931 disclose gabapentin monohydrate and a process for producing the gabapentin monohydrate.
The following table provides a list of abbreviations and definitions thereof used in the present invention:
Preferred compounds of Formula IV prepared by the improved process of the first aspect of the present invention are:
(1-Cyanocyclohexa-2,5-dienyl)acetic acid ethyl ester;
(1-Cyanocyclohexa-2,5-dienyl)acetic acid;
(1-Cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester; and
(1-Cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of Formula IX prepared by the improved process of the fifth aspect of the present invention are:
1-(2,2,2-Trimethoxy-ethyl)-cyclohexa-2,5dienecarbonitrile;
1-(2,2,2-Triethoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile; and
1-(2,2,2-Triisopropoxy-ethyl)-cyclohexa-2,5-dienecarbonitrile.
Preferred compounds of Formula X prepared by the improved process of the fifth aspect of the present invention are:
1-(2,2,2-Trimethoxy-ethyl)-cyclohexanecarbonitrile;
1-(2,2,2-Triethoxy-ethyl)cyclohexanecarbonitrile; and
1-(2,2,2-Triisopropoxy-ethyl)-cyclohexanecarbonitrile.
As previously described, the compound of Formula I is useful for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial trauma.
The process of the present invention in its first aspect is a new, improved, economical, and commercially feasible method for preparing the compound of Formula I. Furthermore, the process can be carried out in a two-pot procedure.
The process of the present invention in its first aspect is outlined in Scheme 1. 
A compound of Formula IV is prepared from benzonitrile (VII) using a Birch reduction, i.e., dissolving metal reduction methodology followed by subsequent alkylation of the anionic intermediate (VI) which is generated in situ.
The alkylation of anions generated in Birch reductions is an established methodology (see xe2x80x9cOrganic Reactionsxe2x80x9d, ed. Paquette L. A., et al., John Wiley and Sons, New York, N.Y., 1992;42:1-334) in organic synthesis. However, there is only one report of the reductive alkylation of benzonitrile (Schultz A. G. and Macielag M., Journal of Organic Chemistry, 1986;51:4983). There is no disclosure of alkylation of these intermediate anions with xcex1-halo acetic acid esters. Though alkylation of nitrites has been disclosed (xe2x80x9cOrganic Reactionsxe2x80x9d, ed. Dauben W. G., et al., John Wiley and Sons. New York, N.Y., 1984:31:1-364), the alkylation of cyclohexanecarbonitrile and cyclohexanecarbonitrile type compounds with xcex1-halo acetic acid esters has not been reported. We have unexpectedly and surprisingly found that the Birch reduction anionic intermediate (VI) is successfully alkylated with xcex1-haloacetic acid and xcex1-haloacetic acid esters in high yields.
Thus, a solution of benzonitrile in a solvent such as, for example, an alcohol such as tertiary butyl alcohol, ethanol, isopropyl alcohol, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether (MTBE) and the like is treated with an alkali metal such as, for example, lithium, sodium, potassium, and the like an amine such as, for example, ammonia and the like at about xe2x88x9278xc2x0 C. to about xe2x88x9233xc2x0 C. for about 0.5 to about 8 hours to generate in situ the anionic intermediate (VI) followed by subsequent treatment with a compound of Formula V wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl to afford a compound of Formula IV wherein R is hydrogen, alkyl, or benzyl. Preferably, the reaction is carried out with lithium in ammonia in tertiary butyl alcohol and tetrahydrofuran.
A compound of Formula IVa wherein R (R1a) is alkyl is treated with hydrogen in the presence of a catalyst such as, for example, rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid, Raney nickel, and Raney cobalt and the like and a solvent such as, for example, methanol and the like to afford a compound of Formula III wherein R1a is alkyl. Preferably, the reaction is carried out with palladium on charcoal and methanol.
A compound of Formula IIIa (R1a is tertiary butyl [t-Bu]) is treated with an acid such as, for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrobromic acid in acetic acid, formic acid, para toluenesulfonic acid, and the like in a solvent such as, for example, dichloromethane, toluene, diethyl ether and the like to afford the compound of Formula II. Preferably, the reaction is carried out with trifluoroacetic acid in dichloromethane.
A compound of Formula IIIb (R1a is alkyl excluding tertiary butyl) is treated with an acid such as, for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like or a base such as, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like or an alkaline earth metal hydroxide, such as calcium hydroxide and the like in a solvent such as, for example, water and/or an alcohol such as methanol, ethanol and the like to afford the compound of Formula II. Preferably, the reaction is carried out with potassium hydroxide in ethanol.
A compound of Formula IVc (R is benzyl [Bn]) is treated with hydrogen in the presence of a catalyst using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula II.
The compound of Formula IVa-1 (R1 is t-Bu) is treated with an acid in the presence of a solvent using the conditions previously described for preparing a compound of Formula II from the compound of Formula IIIa to afford the compound of Formula IVb.
The compound of Formula IVa-2 (R1 is alkyl excluding t-Bu) is treated with an acid or base in the presence of a solvent using the conditions previously described for preparing the compound of Formula II from a compound of Formula IIIb to afford the compound of Formula IVb.
The compound of Formula IVb is treated with hydrogen in the presence of a catalyst using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula II.
The compound of Formula IVb, or the compound of Formula IVc, or the compound of Formula II is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula I.
The process of the present invention in its fifth aspect is a new, improved, economical, and commercially feasible method for preparing the compound of Formula I. The process of the present invention in its fifth aspect is outlined in Scheme 2. 
Thus, the anionic intermediate (VI) is generated in situ as described above followed by subsequent treatment with a compound of Formula VIII wherein X is halo or sulfonate and R2 is alkyl using the conditions previously described for preparing a compound of Formula IV from the compound of Formula VI to afford a compound of Formula IX wherein R2 is as defined above.
A compound of Formula IX is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford a compound of Formula X wherein R2 is as defined above.
A compound of Formula IX is treated with an acid such as, for example, formic acid, acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, para toluenesulfonic acid and the like in a solvent such as, for example, dichloromethane, toluene, tetrahydrofuran, diethyl ether and the like to afford the compound of Formula IVb. Preferably, the reaction is carried out with hydrochloric acid in dichloromethane.
A compound of Formula X is treated with an acid in a solvent using the conditions previously described for preparing the compound of Formula IVb from a compound of Formula IX to afford the compound of Formula II.
The compound of Formula IVb or Formula II is treated with hydrogen in the presence of a catalyst and a solvent using the conditions previously described for preparing a compound of Formula III from a compound of Formula IVa to afford the compound of Formula I.
Compounds of Formula V and Formula VIII are either known or capable of being prepared by methods known in the art.
The following nonlimiting examples illustrate the inventors"" preferred method for preparing the compound of the invention.